Overview of Inflammation

Inflammation, the immune response of body tissues to injury or infection, is an important component of innate immunity. The inflammatory process involves a complex biological cascade of molecular and cellular signals that alter physiological responses, ultimately resulting in the familiar clinical symptoms of pain, swelling, heat, and redness (1, 2). At the site of the injury, cells release molecular signals that cause a number of changes in the affected area: vasodilation, increased blood flow, increased vascular permeability, exudation of fluids containing proteins like antibodies, and invasion by several different types of leukocytes, including granulocytes, monocytes, and lymphocytes(3). Neutrophils are the first leukocytes to appear at the injured site. These cells phagocytose and kill invading microorganisms through the release of non-specific toxins, such as superoxide radicals, hypochlorite, and hydroxyl radicals; these reactive oxygen species (ROS) kill pathogens as well as adjacent cells, sick and healthy alike. Neutrophils also provide additional killing activities by releasing antimicrobial peptides and proteins, such as defensins, cathelicidins and iron-binding proteins, into the phagosome(4). Neutrophils also release cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, γ interferon (INF-γ), and others (3, 5). Such pro-inflammatory cytokines in turn induce the liver to synthesize various acute phase reactant proteins and also induce systemic inflammatory responses (e.g., fever and leukocytosis—a rise in the number of white blood cells) (5).

Acute inflammation is a normal process that protects and heals the body following physical injury or infection. However, if the agent causing the inflammation persists for a prolonged period of time, the inflammation becomes chronic. Chronic inflammation can result from a viral or microbial infection, environmental antigen (e.g., pollen), autoimmune reaction, or persistent activation of inflammatory molecules. Chronic inflammation is primarily mediated by monocytes and long-lived macrophages(3); monocytes mature into macrophages once they leave the bloodstream and enter tissues. Macrophages engulf and digest microorganisms and senescent cells (6). They release several different chemical mediators, including IL-1, TNF-α, and prostaglandins, that perpetuate the pro-inflammatory response. At later stages, other cells, including lymphocytes, invade the affected tissues: T lymphocytes kill virus-infected cells and B lymphocytes produce antibodies that specifically target the invading microorganisms for destruction (3).

Macrophages and other leukocytes release ROS and proteases that destroy the source of inflammation; however, damage to the body's own tissues often results in chronic inflammation. In chronic inflammation, damaged tissues are repaired through replacement with cells of the same type or with fibrous connective tissue. Another important characteristic of chronic inflammation is local angiogenesis—the development of new blood vessels (7). In some instances, the body is unable to repair tissue damage, and the inflammatory cascade continues. Chronic inflammation is abnormal and does not benefit the body; in fact, chronic inflammation is involved in a number of disease states.

Role of Nutrition

One’s diet can affect inflammatory responses within the body; the roles of various dietary components in inflammation are discussed below. Clinical biomarkers of inflammation are used to study the effect of dietary constituents on inflammation. C-reactive protein (CRP), which is an acute phase reactant protein, is a common clinical biomarker of cardiac-related inflammation and also a general marker of inflammation. Other common clinical indicators of inflammation are a high erythrocyte sedimentation rate (ESR), a high white blood cell count, and a low albumin level. However, these tests are nonspecific, meaning an abnormal result might result from a condition unrelated to inflammation. Various cytokines and adhesion molecules are not commonly used clinically because they do not identify the source of inflammation; rather; they are frequently used in scientific research (3,8, 9). Some biomarkers of inflammation are listed in Table 1(10).

In addition to specific dietary factors, achieving and/or maintaining a healthy body weight is critical in the prevention of chronic inflammatory diseases. For instance, elevated CRP levels have been linked to obesity, and weight loss has been shown to decrease CRP levels (11). Obesity and abdominal obesity (also called visceral obesity) are risk factors for several diseases associated with inflammation, i.e., cardiovascular disease, type 2 diabetes mellitus, and metabolic syndrome(12, 13). The causes of these diseases are not completely established, and the role of inflammation in disease pathogenesis is under investigation. For example, it is known that adipose tissue secretes several inflammatory factors (known as adipocytokines or adipokines) and that obesity is associated with macrophage infiltration in adipose tissue (14, 15); however, the exact role of inflammation in the pathogenesis of obesity is currently unknown.

Dietary fats and cholesterol

In general, epidemiological studies have found that diets high in saturated fat and trans fat are pro-inflammatory in nature (reviewed in 16). In contrast, some studies have found that adherence to a Mediterranean-style diet—a diet high in monounsaturated fats—may help reduce inflammation (17, 18). A Mediterranean diet emphasizes olive oil, fruit and vegetables, nuts, beans, fish, whole grains, and moderate consumption of alcohol. Several of these foods are important sources of essential fatty acids that are involved in inflammatory processes. Higher intakes of the omega-3 fatty acids (i.e., α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) have been generally associated with decreased biomarkers of inflammation (19). Rich dietary sources of ALA include flaxseeds and their oil, walnuts and their oil, and canola oil. EPA and DHA are found in oily fish and fish oils (see the article on Essential Fatty Acids). The ratio of omega-6 to omega-3 fatty acids in the typical Western diet is about 15-20:1, yet it is estimated that humans evolved on a diet with an omega-6 to omega-3 fatty acid ratio of about 1:1 (20). Decreasing this ratio will likely reduce the prevalence and severity of various inflammatory conditions observed in Western societies (for more information on dietary fats, see the article on Essential fatty acids(21).

Low cholesterol diets may also reduce inflammation in the body. One study found that a high cholesterol diet (4 eggs/day for four weeks) increased levels of CRP and serum amyloid A (SAA), two inflammatory markers, in lean (BMI <27.5 kg/m2) subjects who were insulin-sensitive but not in lean subjects who were insulin-resistant or in obese (BMI >27.5 kg/m2) individuals; individuals in these two latter groups had elevated baseline levels of CRP and SAA (22). An 8-week intervention study in patients with primary hypercholesterolemia found that a diet low in both cholesterol (<200 mg/day) and saturated fat (5% of dietary fat from saturated fat) was linked to reduced inflammation, evidenced by a 39% reduction in CRP levels (23).

Dietary carbohydrates

Hyperglycemia can cause inflammation through varying mechanisms that result in the production of free radicals and pro-inflammatory cytokines(19, 24). Thus, high glycemic index and glycemic load diets may stimulate inflammation. Glycemic index is the blood glucose-raising potential of the carbohydrates in different foods. A more accurate indicator of the relative glycemic response to dietary carbohydrates, however, is glycemic load. Glycemic load incorporates the relative quality of carbohydrates characterized by the glycemic index. Consumption of high-glycemic index foods results in higher and more rapid increases in blood glucose levels than the consumption of low-glycemic index foods. Rapid increases in blood glucose are potent signals to the β-cells of the pancreas to increase insulin secretion, which can cause a sharp decrease in glucose levels and lead to hypoglycemia(25). In contrast, the consumption of low-glycemic index foods results in lower but more sustained increases in blood glucose and lower insulin demands on pancreatic β-cells (26).

A study in 39 overweight or obese adults found adherence to a low-glycemic index, energy-restricted diet resulted in a 48% decrease in levels of CRP—a common clinical biomarker of cardiac-related inflammation but also a general marker of inflammation (27). Individuals in this study who followed a low-fat, energy-restricted diet experienced only a 5% decline in CRP levels, despite similar weight loss and body composition changes (27). Another small study showed that acute hyperglycemia resulted in increased levels of various pro-inflammatory cytokines; this effect was more pronounced in individuals with impaired glucose tolerance compared to healthy controls (24). More information on the role of dietary carbohydrates in the prevention of chronic diseases, such as cardiovascular disease and diabetes, is available in the article on Glycemic Index and Glycemic Load.

In addition, higher intakes of dietary fiber may protect against the development of diseases with inflammatory components, including cardiovascular disease and type 2 diabetes (28) (see the article on Fiber).

Dietary proteins and amino acids

A number of studies have evaluated the potential of soy protein in the prevention of diseases with inflammatory components (see the article on Soy Isoflavones). Some clinical trials have specifically evaluated the effects of soy protein or soy food consumption on CRP and other inflammatory biomarkers; several such studies have reported overall null effects (29-32).

Analysis of data collected from the Third National Health Nutrition and Examination Survey (NHANES), a US national survey, indicated higher intakes of the amino acid arginine were associated with lower levels of CRP (33). Common sources of arginine in the American diet include meat, poultry, fish, dairy products, eggs, and cereals (34). Nuts, especially peanuts, are also good sources of arginine (35, 36). Regular nut consumption has been shown to be cardioprotective (see the article on Nuts).

The National Health and Nutrition Examination Survey (NHANES) 1999-2000, a US national survey, found American adults who consumed less than the RDA of magnesium were 1.48 to 1.75 times more likely to have elevated CRP levels compared to those who consumed at least the RDA (37). This survey found that 68% of the sample consumed less than the RDA of magnesium (37).

Vitamin B6

Body status of certain vitamins may also affect inflammatory processes. The analysis of data from a cohort of 891 elderly adults participating in the Framingham Heart Study indicated that low vitamin B6 status was associated with higher CRP levels; this association was independent of plasmahomocysteine(38). In this study, vitamin B6 status was assessed by measuring plasma levels of pyridoxal 5’-phosphate (PLP). PLP is the active form of the vitamin and considered to be a good indicator of long-term body stores (39). More recently, plasma PLP levels were inversely associated with CRP levels in a cohort of older Puerto Rican adults (40). A low circulating level of vitamin B6 is a risk factor for cardiovascular disease (see the article on Vitamin B6), and may also be related to rheumatoid arthritis(41-43). However, a double-blind, placebo-controlled trial in 33 patients with rheumatoid arthritis reported that supplementation with 30 mg/day of pyridoxine for 30 days corrected the vitamin B6 deficiency but did not improve specific markers of inflammation, including levels of certain pro-inflammatory cytokines, erythrocyte sedimentation rate, and CRP (44). Moreover, one analysis of data from the NHANES 2003-2004 indicated that dietary intakes at levels corresponding to the current RDA may not result in vitamin B6 adequacy, at least in certain subgroups, such as cigarette smokers, blacks, and the elderly (39).

Vitamin C

Adequate dietary intake of the antioxidant vitamin, vitamin C, is also important because free radicals have pro-inflammatory effects (45). Compared to its antioxidant actions, considerably less is known about whether vitamin C has anti-inflammatory effects (46). A cross-sectional study of 3,258 men (aged 60-79 years) participating in the British Regional Heart Study found that both dietary intake and plasma levels of vitamin C were inversely related to CRP levels (47). Higher vitamin C levels were also associated with lower CRP levels in the NHANES III, which included data from 14,519 US adults (48). A randomized controlled trial in healthy nonsmokers found that vitamin C supplementation (1,000 mg/day) for two months resulted in a 16.7% decrease in median level of CRP in those with elevated CRP levels (= 1.0 mg/L; the level associated with a heightened risk of cardiovascular disease) compared to an 8.6% increase that was seen in the placebo group (49). This trial found no effect of vitamin C supplementation in those with baseline levels of CRP lower than the 1.0 mg/L threshold (49). Several epidemiological studies have examined whether dietary intake, supplemental intake, or serum levels of vitamin C are associated with various cardiovascular disease and gout. Results of many of these studies have indicated that vitamin C may help protect against coronary heart disease and gout—diseases with inflammatory components (see the article on Vitamin C). Additionally, low plasma and leukocyte concentrations of vitamin C have been observed in patients with sepsis—a clinical syndrome characterized by whole-body inflammation that can lead to organ failure (50).

Vitamin D

Several human studies associated vitamin D deficiency or impaired vitamin D status with various inflammatory diseases, such as Crohn’s disease and other inflammatory bowel diseases(55-60). Vitamin D status may also be linked to cardiovascular disease and certain cancers (see the article on Vitamin D). A role for vitamin D in inflammation is supported by studies in laboratory animals. In particular, mice lacking the vitamin D receptor or the vitamin D activating enzyme, 25-hydroxyvitamin D3-1-hydroxylase, have increased susceptibility to inflammation, especially inflammation of the gastrointestinal tract (61-63).

Vitamin E

Vitamin E has effects on inflammatory processes due to the antioxidant functions of α-tocopherol (51). α-Tocopherol exerts anti-inflammatory effects through a number of different mechanisms, for example, by decreasing levels of CRP and pro-inflammatory cytokines and by inhibiting the activity of protein kinase C, an important cell-signaling molecule, and other enzymes, such as cyclooxygenase-2 (51, 52). For information on the role of α-tocopherol in the prevention and treatment of cardiovascular disease, see the article on Vitamin E. Results of some animal studies suggest that vitamin E may also have utility in the treatment of rheumatoid arthritis, but more research in humans is needed (51). In addition, some cell culture and animal studies indicate that γ-tocopherol has anti-inflammatory activities (53, 54).

Multivitamin-mineral supplements

Analysis of a randomized, double-blind, placebo-controlled trial in 87 healthy men and postmenopausal women, who were recruited from the general US population, found that supplementation with a daily multivitamin-mineral for six months was associated with a 14% decrease in CRP levels; a greater magnitude of reduction was seen in those with higher baseline levels of CRP(64). Daily use of a multivitamin-mineral supplement may help improve nutritional status of several micronutrients, which may be of benefit to Americans because, according to a US national survey, over 90% of the population does not meet the EAR for vitamin E, 44% for vitamin A, 31% for vitamin C, and 14% for vitamin B6(65).

Dietary phytochemicals

Carotenoids

Various dietary phytochemicals could affect inflammatory processes within the body. Carotenoids, the yellow, orange, and red pigments synthesized by plants, have a number of different biological activities (see the article on Carotenoids). In one study, the carotenoid β-carotene displayed anti-inflammatory activity by inhibiting pro-inflammatory gene expression through suppressing the activation of NFκ-B, a redox-sensitive transcription factor(66). Specifically, a decrease in expression of various pro-inflammatory genes was seen with β-carotene treatment when an endotoxin was used to induce inflammation in macrophagesin vitro as well as mice in vivo(66). The carotenoids, lycopene and astaxanthin, have also been shown to exhibit anti-inflammatory activities in cell cultures and animal models (67-72). Sources of lycopene include tomatoes, red grapefruit, red watermelon, and guava, while the main dietary sources of astaxanthin include salmon, shrimp, and other seafood (73).

Additionally, the putative anti-inflammatory effect of various carotenoids has been examined in humans. Some epidemiological studies have observed serum levels of certain carotenoids, including α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin, to be inversely associated with circulating levels of CRP, a cardiovascular and general marker of inflammation (74, 75). In a four-week randomized controlled trial in healthy, nonsmoking men, eight daily servings of carotenoid-rich vegetables and fruit were associated with a reduction in CRP levels; the authors of this study did not observe any change in plasma concentrations of vitamins C or E over the four-week period (76). Consumption of fruit and vegetables, in general, has been inversely associated with CRP levels and other biomarkers of inflammation (77-79). In two small intervention trials, consumption of tomato juice or a tomato-based soft drink was associated with decreased markers of inflammation (80, 81), but other dietary components of tomatoes besides lycopene, such as vitamin C, may in part be responsible for any beneficial effects on inflammatory processes (80). Larger clinical trials are needed to determine whether lycopene or other carotenoids help reduce inflammation and risk of associated diseases. For details on carotenoids in the prevention of cardiovascular disease, see the article on Carotenoids.

Flavonoids

Another class of phytochemicals with anti-inflammatory effects includes the flavonoids, a large family of polyphenolic compounds that consists of several subclasses: flavanols, flavonols, flavanones, flavones, isoflavones, and anthocyanidins. For information on common dietary sources of these flavonoids, see the article on Flavonoids. Several in vitro studies and a few in vivo animal studies have shown that various flavonoids, such as quercetin, kaempferol, and genistein, possess anti-inflammatory properties (reviewed in 51 and 82); however, limited studies on the effect of flavonoid intake on inflammatory processes are currently available in humans. In general, bioavailability of flavonoids is relatively low due to poor absorption and rapid elimination. Once absorbed, flavonoids are rapidly metabolized to form various metabolites. Therefore, in vitro studies that use high concentrations and parent compounds (rather than the metabolites) may not be physiologically relevant. Additionally, results of studies employing animal models may not be directly applicable to humans.

Analysis of data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, a cross-sectional study of US adults, indicated that total flavonoid intake was inversely related to serum concentration of CRP(83). Similar inverse associations were found for flavonol, anthocyanidin, and isoflavone intakes as well as intake of select individual flavonoids, including quercetin, kaempferol, genistein, diadzein, malvidin, and peonidin. All of these associations were independent of fruit and vegetable consumption (83). However, a prospective study in a cohort of 38,018 women participating in the Women’s Health Study, followed for almost nine years, did not observe flavonoid intake to be related to plasma concentrations of CRP or risk of developing type 2 diabetes mellitus(84). This study found consumption of flavonoid-rich apples was associated with a significantly reduced risk of type 2 diabetes (84), but such an effect might not necessarily be attributed to flavonoids. Tea also contains high levels of flavonoids, and regular consumption of tea may help prevent chronic diseases associated with inflammation, such as cardiovascular disease and cancer (see the article on Tea).

Other dietary phytochemicals

A six-week, placebo-controlled trial in 20 healthy adults associated consumption of an extract of Polygonum cuspidatum that contained 20% resveratrol (equivalent to 40 mg/day of trans-resveratrol) with decreased plasma levels of TNF-α, a pro-inflammatory cytokine, and reduced nuclear binding of NFκB, a pro-inflammatory transcription factor(85). Other phytochemicals, namely curcumin and garlic-derived compounds, have been shown to exhibit anti-inflammatory properties, mainly in cell culture or animal studies (see the articles on Curcumin and Garlic). Additionally, a high dose of the spice, ginger, has been shown to have anti-inflammatory effects in rats (86). Large-scale, randomized controlled trials are needed to determine the effects of these phytochemicals on inflammatory processes or diseases in humans.

Other dietary compounds

α-Lipoic acid is a naturally occurring compound that is synthesized in small amounts by the body. It is also obtained in the diet from tomatoes, green leafy vegetables, cruciferous vegetables, and other sources. Endogenous α-lipoic acid functions as a cofactor for mitochondrialenzymes important in the generation of energy. When provided as a dietary supplement, however, α-lipoic acid may display a number of other biological activities, including antioxidant and anti-inflammatory functions. Results from studies in cell cultures and animal models have shown the compound has anti-inflammatory properties (reviewed in 87), but human data are extremely limited. A small placebo-controlled trial in patients with metabolic syndrome found that supplementation with α-lipoic acid (300 mg/day) for four weeks resulted in a 15% decline in plasma levels of interleukin-6, an inflammatory marker of atherosclerosis(88).

Lifestyle Factors

Animal and human studies have found that various forms of physical activity decrease both acute and chronic inflammation, as measured by reductions in CRP and certain pro-inflammatory cytokines (89). Moreover, regular physical activity is important in reducing one’s risk for obesity and chronic diseases associated with inflammation (90). However, excessive exercise can increase systemic inflammation. For example, overtraining syndrome in athletes is associated with systemic inflammation and suppressed immune function (91). Several studies have shown that moderate alcohol consumption decreases risk of cardiovascular disease, as well as all-cause mortality (see the article on Alcoholic Beverages). Further, smoking cessation has been reported to decrease CRP and other biomarkers of inflammation (92, 93).

Authors and Reviewers

Written in August 2010 by: Victoria J. Drake, Ph.D. Linus Pauling Institute Oregon State University

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